tbuckley/cabot-search huggingface dataset:
Catalytic Biomaterials and Nanomedicines with Exogenous and Endogenous Activations
Authors: Hui Huang, Zeyu Wang, Liang Chen, Hong Yu, Yu Chen
Journal: Advanced Healthcare Materials (2022)

Catalytic therapy can concurrently enhance therapeutic efficacy and decrease side effects by converting less toxic or nontoxic endogenous substances into various highly toxic reactive species (e.g., toxic radicals) to induce cell apoptosis/necrosis, which has been exploited to combat different types of diseases. As material science and nanotechnology evolve for application in disease therapies, a variety of catalytic biomaterials and nanomedicines have been elaborately designed and synthesized to mediate catalytic reactions and/or enhance the corresponding catalytic treatment efficacy. This review systematically summarizes, outlines, and discusses the state-of-the-art advances in the development and use of catalytic biomaterials and nanomedicines in diverse biomedical applications, particularly concentrating on their endogenous activators, exogenous stimuli (e.g., light, heat, ultrasound, and magnetic field), and the integration of endogenous and exogenous triggers to improve the efficacy of biomaterial/nanomedicine-enabled catalytic treatments. The biosafety and biocompatibility of various catalytic biomaterials and nanomedicines for biomedical applications are also discussed. Finally, the current challenges and future opportunities for advancement of catalytic biomaterials and nanomedicines are highlighted, aiming to boost their early fulfillment of practical clinical applications.
Comparison of a Target Trial Emulation Framework vs Cox Regression to Estimate the Association of Corticosteroids With COVID-19 Mortality
Authors: Katherine L. Hoffman, Edward J. Schenck, Michael J. Satlin, William Whalen, Di Pan, Nicholas Williams, Iván Díaz
Journal: JAMA Network Open (2022)

Communication and adoption of modern study design and analytical techniques is of high importance for the improvement of clinical research from observational data.To compare a modern method for statistical inference, including a target trial emulation framework and doubly robust estimation, with approaches common in the clinical literature, such as Cox proportional hazards models.This retrospective cohort study used longitudinal electronic health record data for outcomes at 28-days from time of hospitalization within a multicenter New York, New York, hospital system. Participants included adult patients hospitalized between March 1 and May 15, 2020, with COVID-19 and not receiving corticosteroids for chronic use. Data were analyzed from October 2021 to March 2022.Corticosteroid exposure was defined as more than 0.5 mg/kg methylprednisolone equivalent in a 24-hour period. For target trial emulation, exposures were corticosteroids for 6 days if and when a patient met criteria for severe hypoxia vs no corticosteroids. For approaches common in clinical literature, treatment definitions used for variables in Cox regression models varied by study design (no time frame, 1 day, and 5 days from time of severe hypoxia).The main outcome was 28-day mortality from time of hospitalization. The association of corticosteroids with mortality for patients with moderate to severe COVID-19 was assessed using the World Health Organization (WHO) meta-analysis of corticosteroid randomized clinical trials as a benchmark.A total of 3298 patients (median [IQR] age, 65 [53-77] years; 1970 [60%] men) were assessed, including 423 patients who received corticosteroids at any point during hospitalization and 699 patients who died within 28 days of hospitalization. Target trial emulation analysis found corticosteroids were associated with a reduced 28-day mortality rate, from 32.2%; (95% CI, 30.9%-33.5%) to 25.7% (95% CI, 24.5%-26.9%). This estimate is qualitatively identical to the WHO meta-analysis odds ratio of 0.66 (95% CI, 0.53-0.82). Hazard ratios using methods comparable with current corticosteroid research range in size and direction, from 0.50 (95% CI, 0.41-0.62) to 1.08 (95% CI, 0.80-1.47).These findings suggest that clinical research based on observational data can be used to estimate findings similar to those from randomized clinical trials; however, the correctness of these estimates requires designing the study and analyzing the data based on principles that are different from the current standard in clinical research.
Multiplexed strategies toward clinical translation of extracellular vesicles
Authors: Junying Song, Baoqiang Song, Lijun Yuan, Guodong Yang
Journal: Theranostics (2022)

Extracellular vesicles (EVs), of which exosomes are a representative subgroup, are naturally secreted nanoparticles with a variety of payloads.With the intrinsic merits of stability, biocompatibility, low immunogenicity, and large capacity, EVs are widely regarded as effective carriers of drug delivery.However, disadvantages, such as low yield, complicated isolation procedures, and low loading efficiency, hinder its clinical translation.In this review, we systematically summarize the advances in EV (especially exosomes) engineering for clinical application, focusing on strategies toward high yield, facile isolation, efficient cargo loading, improved delivery, and optimized manufacturing, which might unleash the infinite power of EVs in clinical translation.
Diabetes Management in Chronic Kidney Disease: A Consensus Report by the American Diabetes Association (ADA) and Kidney Disease: Improving Global Outcomes (KDIGO)
Authors: Ian H. de Boer, Kamlesh Khunti, Tami Sadusky, Katherine R. Tuttle, Joshua J. Neumiller, Connie M. Rhee, Sylvia E. Rosas, Peter Rossing, George Bakris
Journal: Diabetes Care (2022)

People with diabetes and chronic kidney disease (CKD) are at high risk for kidney failure, atherosclerotic cardiovascular disease, heart failure, and premature mortality. Recent clinical trials support new approaches to treat diabetes and CKD. The 2022 American Diabetes Association (ADA) Standards of Medical Care in Diabetes and the Kidney Disease: Improving Global Outcomes (KDIGO) 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease each provide evidence-based recommendations for management. A joint group of ADA and KDIGO representatives reviewed and developed a series of consensus statements to guide clinical care from the ADA and KDIGO guidelines. The published guidelines are aligned in the areas of CKD screening and diagnosis, glycemia monitoring, lifestyle therapies, treatment goals, and pharmacologic management. Recommendations include comprehensive care in which pharmacotherapy that is proven to improve kidney and cardiovascular outcomes is layered on a foundation of healthy lifestyle. Consensus statements provide specific guidance on use of renin-angiotensin system inhibitors, metformin, sodium–glucose cotransporter 2 inhibitors, glucagon-like peptide 1 receptor agonists, and a nonsteroidal mineralocorticoid receptor antagonist. These areas of consensus provide clear direction for implementation of care to improve clinical outcomes of people with diabetes and CKD.
Association of Household Deprivation, Comorbidities, and COVID-19 Hospitalization in Children in Germany, January 2020 to July 2021
Authors: Nico Dragano, Olga Dortmann, Jörg Timm, Matthias Mohrmann, Rosemarie Wehner, Christoph J. Rupprecht, Maria Scheider, Ertan Mayatepek, Morten Wahrendorf
Journal: JAMA Network Open (2022)

Adults in disadvantaged socioeconomic positions have elevated risks of a severe course of COVID-19, but it is unclear whether this holds true for children.To investigate whether young people from disadvantaged households have a higher risk of COVID-19 hospitalization and whether differences were associated with comorbidities that predispose children to severe courses.This population-based cohort study included all children and adolescents (aged 0-18 years) who were enrolled in a statutory health insurance carrier in Germany during the observation period of January 1, 2020, to July 13, 2021. Logistic regressions were calculated to compare children from households with and without an indication of poverty. Age, sex, days under observation, nationality, and comorbidities (eg, obesity, diabetes) were controlled for to account for explanatory factors.Disadvantage on the household level was assessed by the employment status of the insurance holder (ie, employed, long- or short-term unemployed, low-wage employment, economically inactive). Socioeconomic characteristics of the area of residence were also assessed.Daily hospital diagnoses of COVID-19 (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes U07.1 and U07.2) were recorded. Comorbidities were assessed using inpatient and outpatient diagnoses contained in the insurance records.A total of 688 075 children and adolescents were included, with a mean (SD) age of 8.3 (5.8) years and 333 489 (48.4%) female participants. COVID-19 hospital diagnosis was a rare event (1637 participants [0.2%]). Children whose parents were long-term unemployed were 1.36 (95% CI, 1.22-1.51) times more likely than those with employed parents to be hospitalized. Elevated odds were also found for children whose parents had low-wage employment (odds ratio, 1.29; 95% CI, 1.05-1.58). Those living in low-income areas had 3.02 (95% CI, 1.73-5.28) times higher odds of hospitalization than those in less deprived areas. Comorbidities were associated with hospitalization, but their adjustment did not change main estimates for deprivation.In this cohort study, children who had parents who were unemployed and those who lived in low-income areas were at higher risk of COVID-19 hospitalization. This finding suggests that attention must be paid to children with SARS-CoV-2 from vulnerable families and closer monitoring should be considered. A number of explanatory factors, including comorbidities, were taken into account, but their analysis yielded no clear picture about underlying processes.
Long-term Outcomes Among Young Adults With Type 2 Diabetes Based on Durability of Glycemic Control: Results From the TODAY Cohort Study
Authors: Janine Higgins, Steven D. Chernausek, Laure El Ghormli, Elvira Isganaitis, Megan M. Kelsey, Marsha D. Marcus, Siripoom McKay, Maggie Siska, Shylaja Srinivasan, Rose Gubitosi-Klug
Journal: Diabetes Care (2022)

OBJECTIVE To examine the effect of different patterns of durable glycemic control on the development of comorbidities among youth with type 2 diabetes (T2D) and to assess the impact of fasting glucose (FG) variability on the clinical course of T2D. RESEARCH DESIGN AND METHODS From the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study, 457 participants (mean age, 14 years) with mean diabetes duration &amp;lt;2 years at entry and a minimum study follow-up of 10 years were included in these analyses. HbA1c, FG concentrations, and β-cell function estimates from oral glucose tolerance tests were measured longitudinally. Prevalence of comorbidities by glycemic control status after 10 years in the TODAY study was assessed. RESULTS Higher baseline HbA1c concentration, lower β-cell function, and maternal history of diabetes were strongly associated with loss of glycemic control in youth with T2D. Higher cumulative HbA1c concentration over 4 years and greater FG variability over a year within 3 years of diagnosis were related to higher prevalence of dyslipidemia, nephropathy, and retinopathy progression over the subsequent 10 years. A coefficient of variability in FG ≥8.3% predicted future loss of glycemic control and development of comorbidities. CONCLUSIONS Higher baseline HbA1c concentration and FG variability during year 1 accurately predicted youth with T2D who will experience metabolic decompensation and comorbidities. These values may be useful tools for clinicians when considering early intensification of therapy.
Clarifying the Association of Individual Factors With Medical School Attrition
Authors: Yi-Chia Chen, Ping-I Lin
Journal: JAMA Pediatrics (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Pediatrics HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Pediatrics journal
A (Controlled) Spill of IL2 for Localized Treatment of Mesothelioma
Authors: Rohan Palanki, Kelsey L. Swingle, Michael J. Mitchell
Journal: Clinical Cancer Research (2022)

A microencapsulated, cell-based IL2 cytokine factory was recently developed, and the safety and efficacy of this platform in a mouse model of mesothelioma were demonstrated. This platform has the potential to overcome current challenges in the delivery of therapeutic cytokines for cancer immunotherapy. See related article by Nash et al., p. 5121.
A Phase I/II Trial of Nivolumab plus Ipilimumab in Children and Young Adults with Relapsed/Refractory Solid Tumors: A Children's Oncology Group Study ADVL1412
Authors: Kara L. Davis, Elizabeth Fox, Emasenyie Isikwei, Joel M. Reid, Xiaowei Liu, Charles G. Minard, Stephan Voss, Stacey L. Berg, Brenda J. Weigel, Crystal L. Mackall
Journal: Clinical Cancer Research (2022)

In many cancers, nivolumab in combination with ipilimumab improves response rates compared with either agent alone, but the combination has not been evaluated in childhood cancer. We conducted a phase I/II trial of nivolumab plus ipilimumab in children and young adults with recurrent/refractory solid tumors.ADVL1412, Part C assessed safety of nivolumab plus ipilimumab at two dose levels (DL): DL1 1 mg/kg of each drug and DL2 3 mg/kg nivolumab plus 1 mg/kg ipilimumab. Part D evaluated response at the recommended phase II dose (RP2D) in Ewing sarcoma, rhabdomyosarcoma, and osteosarcoma. Part E tested DL3 (1 mg/kg nivolumab plus 3 mg/kg ipilimumab) in Ewing sarcoma and rhabdomyosarcoma. Tumor response was measured using RECIST v1.1. Pharmacokinetics and PD-L1 expression on archival tissues were assessed.Fifty-five eligible patients enrolled. Based on safety, tolerability, and similar drug exposure to the same doses administered in adults, DL2 was defined as the pediatric RP2D. Among 41 patients treated at the RP2D, 2 patients experienced dose-limiting toxicities during cycle 1, and 4 patients experienced toxicities beyond that period. Two patients had clinically significant sustained partial responses (1 rhabdomyosarcoma, 1 Ewing sarcoma) and 4 had stable disease. Among 8 patients treated at DL3, 3 dose-limiting toxicities (DLT) occurred, all immune-related adverse events; no objective responses were observed.The RP2D of nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) is well tolerated in children and young adults with solid tumors and shows some clinical activity. Increased dose of ipilimumab (3 mg/kg) plus nivolumab (1 mg/kg) was associated with increased toxicity without clinical benefit.
Fulfillment of Postmarket Commitments and Requirements for New Drugs Approved by the FDA, 2013-2016
Authors: Beatrice L. Brown, Mayookha Mitra-Majumdar, Jonathan J. Darrow, Osman Moneer, Catherine Pham, Jerry Avorn, Aaron S. Kesselheim
Journal: JAMA Internal Medicine (2022)

This cohort study used the Drugs@FDA database to identify new drugs approved by the US Food and Drug Administration (FDA) and assess fulfillment of postmarket commitments and requirements.
Comprehensive overview of Nrf2-related epigenetic regulations involved in ischemia-reperfusion injury
Authors: Jun Zhang, Wanqian Pan, Yue Zhang, Mingyue Tan, Yunfei Yin, Yuanmei Li, Lei Zhang, Lianhua Han, Jiaxiang Bai, Tingbo Jiang, Hongxia Li
Journal: Theranostics (2022)

Ischemic disease is a class of diseases in which an organ is ischemic due to vascular occlusion, a major contributor to death and disability worldwide.However, when the blood flow is restored, more severe damage occurs than ischemia alone and is known as ischemic-reperfusion injury (IRI).During reperfusion, the imbalance between the production of reactive oxygen species (ROS) and buffering capacity of the antioxidant defense system results in cell damage and death.Nuclear factor E2-related factor 2 (Nrf2) significantly affects antioxidant stress damage.The function of Nrf2 in the pathological process of IRI has been widely discussed, but the impact of epigenetic modifications associated with Nrf2 remains unclear.This article provides a comprehensive overview of the role and mechanism of Nrf2-related epigenetic modifications in the IRI of various organs, including the brain, heart, liver, and kidney.In addition, we summarize agonists that may target epigenetic regulation of Nrf2, which may be beneficial in seeking more effective strategies to improve IRI.
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Authors: Mytien Nguyen, Mayur Desai, Dowin Boatright
Journal: JAMA Pediatrics (2022)

Susan Hillis, PhD; Joel-Pascal Ntwali N’konzi, MSc; William Msemburi, PhD; Lucie Cluver, PhD; Andrés Villaveces, MD, PhD; Seth Flaxman, PhD; H. Juliette T. Unwin, PhD
Kir6.1/K-ATP channel in astrocytes is an essential negative modulator of astrocytic pyroptosis in mouse model of depression
Authors: Feng Li, Si-Yuan Jiang, Tian Tian, Wen-Jie Li, You Xue, Ren-Hong Du, Gang Hu, Ming Lu
Journal: Theranostics (2022)

Rationale: Astrocyte dysfunction is one of the important pathological mechanisms of depression. Stress contributes to the onset of depression. As metabolic stress sensor, Kir6.1-contaning K-ATP channel (Kir6.1/K-ATP) is prominently expressed in astrocytes. However, the involvement of Kir6.1/K-ATP channel in depression remains obscure. Methods: Astrocyte-specific Kir6.1 knockout mice were used to prepare two mouse models of depression to explore the role of astrocytic Kir6.1/K-ATP channel in depression. Primary astrocytes were cultured to reveal the underlying mechanism for Kir6.1-regulated astrocytic pyroptosis. Results: We identified that chronic stress reduced the astrocytic Kir6.1 expression in hippocampus of mice. We further observed astrocyte-specific knockout of Kir6.1 induced depressive-like behaviors in mice. Moreover, we found that astrocytic Kir6.1 deletion increased NLRP3-mediated astrocytic pyroptosis in response to stress. Mechanistically, Kir6.1 associated with NLRP3, and this interaction prevented the assembly and activation of NLRP3 inflammasome, thereby inhibition of astrocytic pyroptosis. More importantly, VX-765, an effective and selective inhibitor for NLRP3 inflammasome, could reverse the astrocytic pyroptosis and rescue the deterioration of behaviors in astrocytic Kir6.1 knockout mice. Conclusions: Our findings illustrate that Kir6.1/K-ATP channel in astrocytes is an essential negative modulator of astrocytic pyroptosis and plays a crucial role in depression and suggest that astrocytic Kir6.1/K-ATP channel may be a promising therapeutic target for depression.
System-wide vitreous proteome dissection reveals impaired sheddase activity in diabetic retinopathy
Authors: Asfa Alli-Shaik, Beiying Qiu, Siew Li Lai, Ning Cheung, Gavin Tan, Suat Peng Neo, Alison Tan, Chiu Ming Gemmy Cheung, Wanjin Hong, Tien Yin Wong, Xiaomeng Wang, Jayantha Gunaratne
Journal: Theranostics (2022)

Rationale: Diabetic retinopathy (DR) is a major complication of diabetes mellitus causing significant vision loss. DR is a multifactorial disease involving changes in retinal microvasculature and neuronal layers, and aberrations in vascular endothelial growth factors (VEGF) and inflammatory pathways. Despite the success of anti-VEGF therapy, many DR patients do not respond well to the treatment, emphasizing the involvement of other molecular players in neuronal and vascular aberrations in DR. Methods: We employed advanced mass spectrometry-based proteome profiling to obtain a global snapshot of altered protein abundances in vitreous humor from patients with proliferative DR (PDR) in comparison to individuals with epiretinal membrane without active DR or other retinal vascular complications. Global proteome correlation map and protein-protein interaction networks were used to probe into the functional inclination of proteins and aberrated molecular networks in PDR vitreous. In addition, peptide-centric analysis of the proteome data was carried out to identify proteolytic processing, primarily ectodomain shedding events in PDR vitreous. Functional validation experiments were performed using preclinical models of ocular angiogenesis. Results: The vitreous proteome landscape revealed distinct dysregulations in several metabolic, signaling, and immune networks in PDR. Systematic analysis of altered proteins uncovered specific impairment in ectodomain shedding of several transmembrane proteins playing critical roles in neurodegeneration and angiogenesis, pointing to defects in their regulating sheddases, particularly ADAM10, which emerged as the predominant sheddase. We confirmed that ADAM10 protease activity was reduced in animal models of ocular angiogenesis and established that activation of ADAM10 can suppress endothelial cell activation and angiogenesis. Furthermore, we identified the impaired ADAM10-AXL axis as a driver of retinal angiogenesis. Conclusion: We demonstrate restoration of aberrant ectodomain shedding as an effective strategy for treating PDR and propose ADAM10 as an attractive therapeutic target. In all, our study uncovered impaired ectodomain shedding as a prominent feature of PDR, opening new possibilities for advancement in the DR therapeutic space.